An international team of AIDS researchers at Johns
Hopkins and other institutions has found that a once-daily
combination of three antiretroviral drugs works better as
an initial treatment for HIV infection than another
three-drug combination long considered the gold
standard.

Reporting in the Jan. 19 issue of The New England
Journal of Medicine, the researchers showed that after
one year of treatment, a regimen of antiretroviral pills
called tenofovir DF (Viread) and emtricitabine (Emtriva),
plus efavirenz (Sustiva) led to 14 percent more patients
able to suppress levels of the virus, with fewer problems
of anemia, fatigue and nausea than another, widely used
combination of antiretrovirals — zidovudine and
lamivudine (AZT and 3TC, or Combivir), plus efavirenz.

"The implications are quite clear for patients with
HIV who are about to start therapy: The simple combination
of tenofovir and emtricitabine, plus efavirenz, is likely
to be highly potent with minimal side effects or long-term
toxicity," said the study's lead author, Joel Gallant,
associate professor and associate director of the
AIDS Service at
the Johns Hopkins School of Medicine. Gallant noted that
this regimen became even simpler in 2004, when tenofovir
and emtricitabine were combined into a single pill called
Truvada.

The Centers for Disease Control and Prevention
estimates that 40,000 Americans are newly infected each
year with the virus that causes AIDS. Another quarter
million already have HIV and are unaware of their infection
and need for treatment.

Gallant cautioned that the latest results may not
apply to those patients already on zidovudine lamivudine
therapy and experiencing no problems. However, he pointed
out that after the first year of the study, expected to
continue for another two years, data already show early
evidence of lipoatrophy (fat loss) in patients taking this
regimen. Lipoatrophy is a known complication of some HIV
medications that can lead to disfiguring changes in body
shape. The researcher said that if fat loss gets worse
during the remainder of the study in patients taking the
zidovudine lamivudine regimen, this would support switching
them to the tenofovir emtricitabine regimen.

Tenofovir DF and emtricitabine are relatively new
drugs, approved by the Food and Drug Administration in 2001
and 2003, respectively. Zidovudine was the first
antiretroviral drug, approved in 1987, and lamivudine
became available in 1995. Since 1998, zidovudine and
lamivudine have been available in a single pill formulation
called Combivir, which is prescribed as one pill taken
twice daily.

In this study, both combinations included efavirenz,
which, like the other drugs, prevents the genetic material,
or RNA, in HIV from being turned into DNA. Efavirenz has
been widely used for initial therapy since its approval in
1998.

Gallant's study results are believed to be the first
to demonstrate superiority of any regimen over the
combination of zidovudine, lamivudine and efavirenz, which
has been a popular and recommended combination for many
years. The latest guidelines from the U.S. Department of
Health and Human Services, released in 2005, recommend
either combination as a preferred initial treatment for HIV
disease.

The study, known as Study 934, involved 517 patients
from 67 sites across the United States, France, Germany,
Italy, Spain and the United Kingdom. Participants were men
and women of all races, with an average age of 36, none of
whom had been treated for their HIV infection. Half had
viral loads in excess of 100,000 copies per milliliter of
blood. Each participant was randomly assigned to start
treatment with either the tenofovir emtricitabine or
zidovudine lamivudine regimen, each in combination with
efavirenz. Their progress was monitored through blood
tests, pill counts and regular checkups at their medical
clinic.

Researchers found at the end of the first year of
treatment that 80 percent of patients receiving the
tenofovir emtricitabine combination were able to suppress
viral loads to undetectable levels (less than 50 copies per
milliliter of blood), compared to 70 percent in the
zidovudine lamivudine group.

As viral levels dropped, the immune systems of
patients who received the tenofovir emtricitabine regimen
also rebounded most, as measured by the increase in CD4
cells, which help fight infection. Their CD4 counts
increased by an average of 190 cells per cubic millimeter
of blood, while the average increase in the zidovudine
lamivudine group was 158 cells per cubic millimeter of
blood.

"Both treatments are effective," Gallant said. "But
this study shows that we can do better, with fewer side
effects and greater simplicity."

More side effects were reported in the zidovudine
lamivudine group, with 9 percent having to withdraw from
the study, compared to just 4 percent in the tenofovir
emtricitabine group. The most common reason for stopping
therapy in the zidovudine lamivudine group was anemia, or
loss of red blood cells. Discontinuation due to nausea,
fatigue and dizziness, other side effects of zidovudine,
was also more common with this regimen.

A subgroup of 100 patients had specialized tests to
measure the amount of fat in the limbs at the end of the
study. Patients in the zidovudine lamivudine group had
significantly less fat in their limbs by an average of more
than four pounds, which may be a result of lipoatrophy, a
recognized long-term side effect of zidovudine.

Study 934 quickly follows the results of previous
research, Study 903, published by Gallant in July 2004 in
the Journal of the American Medical Association, which
showed that tenofovir DF was equally effective but had
fewer side effects than another antiretroviral drug called
stavudine (d4T, Zerit).

Adherence to taking pills as prescribed in Study 934
was also better in the tenofovir emtricitabine group, at 90
percent, than for the zidovudine lamivudine group, at 87
percent. Gallant attributes some of this difference to the
fact that the former regimen could be taken once daily and
was less likely to cause nausea than the latter
combination, which had to be taken twice daily.

While Gallant noted that antiretroviral drug regimens
have dramatically decreased in complexity in the last 10
years, he said that it would not have been unusual in 1996
for patients to have been taking combinations of up to 24
pills per day, in as many as five daily doses and often
with complicated food restrictions. However, the drug
regimen in Study 934, he added, required that patients take
just two pills per day without any food restrictions. The
three drugs should be available in a single pill
formulation within the year.

"The steady progress we have seen in simplifying
antiretroviral therapy should make it a lot easier for
patients to be adherent, which is critical to having a
prolonged response and avoiding drug resistance," the
researcher said.

Drug resistance was not a significant factor for
either drug combination in the study. However, Gallant
noted that 22 patients were later found to have been
resistant to efavirenz before starting medications, and
these patients did not do as well on therapy as the overall
group.

"This highlights the importance of testing for drug
resistance before choosing a drug regimen, so the initial
combination can be tailored based on the patient's
resistance results," he said.

Tenofovir is the only nucleotide reverse transcriptase
inhibitor, but it is closely related to emtricitabine,
zidovudine and lamivudine, which belong to a class of
medications called nucleoside reverse transcriptase
inhibitors. These drugs are combined with other AIDS drugs,
either non-nucleoside reverse transcriptase inhibitors,
such as efavirenz, or with protease inhibitors, which were
not used in this study.

Funding for this research was provided by Gilead
Sciences, of Foster City, Calif., the makers of the drugs
tenofovir DF and emtricitabine. Gallant is a paid
consultant to Gilead as well as to GlaxoSmithKline, which
manufactures the zidovudine lamivudine combination. He is
also a paid consultant to other drug manufacturers,
including Bristol Myers Squibb, which manufactures
efavirenz. The terms of these arrangements are being
managed by Johns Hopkins in accordance with its
conflict-of-interest policies.